ETV6 Deficiency and Microsatellite Enhancers Drive Transcriptional Dysregulation in B-Lymphoblastic Leukemia: ChIP-Seq data

Distal enhancers play critical roles in sustaining oncogenic gene expression programs. We obtained ATAC-Seq data and ChIP-Seq data using antibodies against the H3K27ac histone mark, transcription factors ERG and ETV6, and input chromatin from B-ALL cell lines and comparator B-cell cancer cell lines, including B-ALL with biallelic ETV6 inactivation, ETV6-RUNX1, and intact ETV6. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+ B-ALL “signature” genes, including likely oncogenic drivers. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of many repeat enhancer-activated genes. Together, our findings reveal a novel epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene expression program of ETV6-RUNX1+ B-ALL. ChIP-Seq datasets were aligned to hg38. De novo peak calling was performed on TF ChIP-Seq datasets. Both TF and H3K27ac ChIP-Seq datasets were used to compare normalized signal across cell lines and experimental conditions for loci of interest.